Treatment of alcohol use disorders (AUDs), commonly referred to as alcoholism, has been hampered by alcohol's promiscuous pharmacological effects and the complex etiology of addiction. People drink in excess for a variety of reasons, and an approach that targets more of these reasons will have greater commercial success than an approach that only targets a sole aspect. Excessive consumption of alcohol results in many changes in the brain that contribute to the development of addiction including progressive neurodegeneration and impaired executive function, and dependence that leads to withdrawal-induced negative affect. However, of the three drugs currently approved by the FDA for the treatment of excessive alcohol consumption, none address neurodegeneration, withdrawal or anxiety. Whereas recently success has been seen in a class of drugs that are neuroprotective in many neurodegenerative disease models, the cannabinoids. Intriguingly, this class of drugs, and specifically cannabidiol (CBD), also has anticonvulsant (withdrawal) and anxiolytic properties that make it an ideal candidate for the treatment of AUDs. The cannabinoid class of compounds has been minimally studied because of the lack of a suitable drug delivery method. Oral delivery of drugs is usually the preferred administration route, however the oral bioavailability of CBD is only about 6%. Therefore, the transdermal delivery route will be used in order to provide substantial plasma CBD levels with the added convenience of controlled release delivery. This proposal will test the overall hypothesis that transdermal delivery of a cannabinoid, cannabidiol, may protect against alcoholic neural and behavioral pathologies by determining (1) if transdermal delivery of cannabidiol can prevent alcohol-induced neurodegeneration in an established rat model of binge drinking. In this aim, we will refine transdermal delivery of CBD and examine its effects on both cell death via examination of Fluoro-Jade B labeling of degenerating cells and cell birth via examination of labeling of neural progenitor/stem cell proliferation and (2) whether transdermal delivery of cannabidiol can prevent alcohol-induced behavioral pathology in a rat model of binge drinking. Behavioral pathologies associated with AUDs include preoccupation with the drug (perseveration) and negative affect (anxiety) as the result of withdrawal from the drug. Both behaviors may then drive drug seeking to alleviate these symptoms and thus are leading candidates as targets of relapse prevention. Therefore, in this aim, we examine the effect of transdermal delivery of CBD on withdrawal severity including seizures, withdrawal- induced anxiety on the Elevated Plus Maze and perseverative behavior on the Morris Water Maze following binge alcohol exposure. With over 8.5% of the population meeting the diagnostic criteria for alcohol use disorders (AUDs), alcohol use and abuse are one of the nation's major public health problems. Currently approved pharmacological treatments have only targeted the craving aspect of addiction, an approach that has failed a large portion of alcoholics. Thus, the treatment of alcoholism would benefit from a pharmacological approach designed to target multiple aspects of alcoholism: neurodegeneration, withdrawal and anxiety. Cannabidiol administration in the appropriate delivery system has these benefits as a lead candidate in the search for novel alcoholism pharmacotherapies. [unreadable] [unreadable] [unreadable]